Cardiovascular disease is a major health risk throughout the industrialized world. An estimated 81.1 million Americans suffer from one or more types of cardiovascular disease, including high blood pressure, coronary heart disease, heart failure, and stroke (Heart Disease and Stroke Statistics, American Heart Association, 2010). Cardiovascular disease is one of the leading causes of death in Americans.
Among cardiovascular diseases, ischemic heart disease is the most common cause of death in most western countries. Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. One serious condition is myocardial infarction (MI), commonly known as a heart attack. Estimates for 2006 show that 8.5 million people in the United States suffer from MI (Heart Disease and Stroke Statistics, American Heart Association, 2010). MI is caused by a sudden and sustained lack of blood flow to an area of the heart, typically caused by narrowing of a coronary artery. Without adequate blood supply, the tissue becomes ischemic, leading to the death of myocytes and vascular structures. This area of necrotic tissue is referred to as the infarct site, the size of which determines survival, with the probability of recovery decreasing with increasing infarct size. For example, in humans, an infarct of 46% or more of the left ventricle triggers irreversible cardiogenic shock and death.
Although an ischemic injury can initiate a healing process, it leads to formation of a scar that does not possess the biochemical, physical and functional properties of the original myocardial tissue, and therefore, negatively affects the overall performance of the heart. These myocardial alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. Leri A et al, 85 Physiol Rev. 1373 (2005).
Previous studies have discussed that hematopoietic stem cells may improve the outcome of myocardial infarction in animal models (1-3). Bone marrow mononuclear cells, CD34-positive cells and mesenchymal stromal cells have been introduced clinically with rather consistent results. The intracoronary or intramyocardial injection of these cell classes has been shown to be safe and to produce a modest enhancement in systolic function (4-6). More recently, there is mounting evidence to suggest that the heart has regenerative potential in the event of myocardial injury. Recent studies have identified resident cardiac stem cells (CSCs) in the human heart (7, 8). Thus, regeneration of myocardial tissue after acute infarction has been attempted by employing CSCs. For example, implantation of growth factor-treated CSCs to the damaged myocardium or local activation of resident CSCs by intramyocardial administration of growth factors, e.g., insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF), has been recently shown to have a possibility of recovering ventricular muscle mass in an in vivo model. Linke A et al., 102 PNAS 8966 (2005); Urbanek K et al., 97 Circ Res. 663 (2005); Rota M et al., 103 Circ Res. 107 (2008). However, regeneration of a functional myocadium by IGF-1 or HGF-treated CSCs is limited by CSC differentiation into mature and functionally competent myocytes.
The identification of resident cardiac stem cells in the human heart (7, 8), together with the isolation of a complex pool of cardiac cells, namely the cardiospheres (9), has implicated a potential implementation of these autologous cells for the management of the human disease. For example, preclinical studies have been completed and two phase 1 clinical trials in patients affected by acute (Identifier: NCT00893360) and chronic (Identifier: NCT00474461) ischemic cardiomyopathy are in progress. No information is currently available on the efficacy of human cardiac stem cells (hCSCs) in these pathological conditions. However, the age of the patient and the type and duration of the disease may affect the number and growth properties of these primitive cells. For instance, telomere attrition, cellular senescence and apoptosis all contribute to decrease the compartment of functionally-competent hCSCs in the old failing heart (10-12). Further, age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Accordingly, reconstitution of muscle mass by cell implantation after infarction is limited by two factors: number of cells engrafted into the recipient myocardium and modest differentiation of the cardiomyocyte progeny. As such, there is a strong need to develop methods to address the foregoing issues. Such methods would significantly improve stem cell-mediated treatment of heart diseases, e.g., myocardial infarctions, and provide new approaches to the management of human heart failure.